Abstract
Abstract 257
The AML-12 randomized phase III trial of EORTC-LG and GIMEMA assessed the efficacy and toxicity of HD-AraC (3 g/sqm/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm/d for 3 days) and etoposide (50 mg/sqm/d for 5 days) vs SD-AraC (100 mg/sqm/d for 10 days) with the same drugs, in previously untreated AML < 61 year old patients (APL excluded). Patients (pts) in complete remission (CR) had to receive consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin. Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability and age. A 2nd randomization had to be done after evaluation of consolidation in pts without a donor: auto-SCT followed or not by low dose IL-2. The aim of the trial was to detect an 8% treatment difference (from 35% to 43%) in the 5-yr overall survival (OS) rate, corresponding to a hazard ratio (HR) of 0.80 (alpha=5%, power=95%); secondary endpoints were response to induction, toxicity, disease-free survival (DFS) from CR. Randomization was performed centrally; the 1st randomization was stratified for age (<46 vs > 45 yrs), performance status, WBC and center. Intent-to-treat analysis was done. From 9/1999 till 1/2008, 2005 pts from 68 centers were randomized. Due to insufficient reporting, 3 centers, who recruited 63 patients, have been excluded from the analysis. The remaining 1942 pts (872 pts entered by EORTC-LG and 1070 by GIMEMA) 969 were randomized in SD-AraC and 973 in HD-AraC arm; among them 25 and 28, respectively, were ineligible, but kept in the analysis. Both arms were comparable with respect to gender, age (median=45 yrs), disease history, initial leukocyte count, PS, FAB and cytogenetics. At a median follow up of 6 yrs, 1114 pts had died.
After 1 or 2 courses of induction, CR was achieved in 1430 pts (73.6%); 684 (71.9%) pts (SD-AraC group) vrs 746 (78.7%) pts (HD-AraC group): p=0.002. Resistance was documented in 173 (18.2%) vrs 123 (13%), and death during induction in 85 (8.9%) vrs 71 (7.5%) pts, respectively. Induction toxicity profile and grade was similar in the 2 arms except for conjunctivitis grade 3: HD-AraC>SD-AraC. CR rates for pts<46 yrs were 74.7% (SD-AraC) and 81.4% (HD-AraC) and for pts>45 yrs 66.4% (SD-AraC) and 71.8% (HD-AraC). 634 pts (SD-AraC and 686 (HD-AraC) received a consolidation cycle. Among 765 CR-pts<46 yrs 284 pts had an HLA identical sibling (<46D) and 481 did not or had not been typed (<46NoD). Among 665 CR-pts>45 yrs 225 pts had an HLA identical sibling (>45D) and 440 did not or had not been typed (>45NoD). In the <46D group 211 underwent an allo-SCT and 11 an auto-SCT. In the <46NoD group 274 underwent an auto-SCT and 29 a MUD-SCT; in the >45D group 147 underwent an allo-SCT and 14 an auto-SCT. In the >45NoD group 244 underwent an auto-SCT and 12 a MUD-SCT. Comparisons of treatments arm regarding OS from randomization, DFS and Survival (S) from CR are indicated in the Table.
| Endpoint . | All patients . | Age < 46 . | Age >45 . | |||
|---|---|---|---|---|---|---|
| SD-Ara-C . | HD-Ara-C . | SD-Ara-C . | HD-Ara-C . | SD-Ara-C . | HD-Ara-C . | |
| OS: 6-yr rate | 38.7% | 42.5% | 43.4% | 51.9% | 33.9% | 32.9% |
| OS: HR (CI)* | 0.89 (0.79–1.00) | 0.79 (0.63–1.00) | 0.99 (0.81–1.22) | |||
| OS: p-value** | 0.06 | 0.009 | 0.91 | |||
| DFS: 6-yr rate | 41.5% | 44.7% | 46.4% | 52.8% | 35.7% | 35.6% |
| DFS: HR (CI)* | 0.92 (0.80–1.06) | 0.83 (0.64–1.08) | 1.02 (0.80–1.32) | |||
| DFS: p-value** | 0.25 | 0.07 | 0.80 | |||
| S from CR: 6-yr rate | 50.2% | 51.8% | 55.2% | 60.7% | 44.4% | 41.7% |
| S from CR: HR (CI)* | 0.95 (0.81–1.10) | 0.85 (0.63–1.14) | 1.05 (0.80–1.37) | |||
| S from CR: p-value** | 0.48 | 0.15 | 0.66 | |||
| Endpoint . | All patients . | Age < 46 . | Age >45 . | |||
|---|---|---|---|---|---|---|
| SD-Ara-C . | HD-Ara-C . | SD-Ara-C . | HD-Ara-C . | SD-Ara-C . | HD-Ara-C . | |
| OS: 6-yr rate | 38.7% | 42.5% | 43.4% | 51.9% | 33.9% | 32.9% |
| OS: HR (CI)* | 0.89 (0.79–1.00) | 0.79 (0.63–1.00) | 0.99 (0.81–1.22) | |||
| OS: p-value** | 0.06 | 0.009 | 0.91 | |||
| DFS: 6-yr rate | 41.5% | 44.7% | 46.4% | 52.8% | 35.7% | 35.6% |
| DFS: HR (CI)* | 0.92 (0.80–1.06) | 0.83 (0.64–1.08) | 1.02 (0.80–1.32) | |||
| DFS: p-value** | 0.25 | 0.07 | 0.80 | |||
| S from CR: 6-yr rate | 50.2% | 51.8% | 55.2% | 60.7% | 44.4% | 41.7% |
| S from CR: HR (CI)* | 0.95 (0.81–1.10) | 0.85 (0.63–1.14) | 1.05 (0.80–1.37) | |||
| S from CR: p-value** | 0.48 | 0.15 | 0.66 | |||
: CI = confidence interval; 95% CI – all patients – and 99% CI – by age -;
logrank test
The impact of age on the treatment difference regarding OS was almost significant (p=0.06). In pts >45 who reached CR, the decrease in the relapse rate in the HD-Ara-C arm vrs SD-Ara-C arm (45.5% vs 49.4%) was counterbalanced by an increase in the death in CR rate (18.4% vs 13.2%).
The final evaluation of the EORTC-GIMEMA AML-12 trial shows that, with a median follow-up of 6 years, HD-AraC in the induction treatment leads to a significantly higher CR rate than SD-Ara-C and results in improvement in overall survival but only in pts under the age of 46 years.
Muus:Amgen: Membership on an entity's Board of Directors or advisory committees. Beksac:Janssen Cilag: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau.
Author notes
Asterisk with author names denotes non-ASH members.
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